Targeting the anaphase-promoting complex/cyclosome (APC/C)- bromodomain containing 7 (BRD7) pathway for human osteosarcoma
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Kaishun Hu1,*, Dan Liao1,*, Wenjing Wu1,*, An-Jia Han2, Hui-Juan Shi2, Fen Wang2, Xin Wang1,Li Zhong1, Tingmei Duan 1, Yuanzhong Wu1, Jingying Cao1, Jianjun Tang1, Yi Sang1, Li Wang1, Xiaobin Lv1, Shuangbing Xu1, Ru-Hua Zhang1, Wu-Guo Deng1, Sheng-Ping Li1, Yi-Xin Zeng1, and Tiebang Kang1
1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China, ;
2 Department of Pathology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China;
* These authors contributed equally to the work
Tiebang Kang, email:
Keywords: APC/C, BRD7, Cancer Target
Received: January 15, 2014 Accepted: March 19, 2014 Published: March 21, 2014
Osteosarcoma is the most common primary malignant bone tumor in childhood and adolescence and has a propensity for local invasion and early lung metastasis. However, the current therapies often result in chemoresistance, and a therapeutic target is not available in the clinic for osteosarcoma. Here, we report that BRD7 forms a complex with the anaphase-promoting complex/cyclosome (APC/C) and is degraded by APC/Ccdh1 and APC/Ccdc20 during the cell cycle. Moreover, BRD7 is a tumor suppressor in osteosarcoma, and the BRD7 mutant resistant to degradation by APC/C is more efficient than the wild-type protein at suppressing proliferation, colony formation, and tumor growth of osteosarcoma in vitro and in vivo. The combination of proTAME, an inhibitor of APC/C, with chemotherapeutic drugs efficiently targets osteosarcoma in vitro. Furthermore, there is a strong inverse correlation of protein levels between BRD7 and Cdh1 or Cdc20, and lower BRD7 expression is an indicator for poor prognosis in patients with osteosarcoma. Collectively, our results indicate that targeting the APC/C-BRD7 pathway may be a novel strategy for treating osteosarcoma.
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